Colorectal cancer (CRC) is the third most common malignancy and fourth most common cause of mortality worldwide, and there is an urgent need of new therapeutic approaches for this devastating disease. Although many signaling pathways with important roles in CRC have been identified, there are still major gaps in our understanding about how these pathways functionally network and interplay during malignant transformation of the intestinal epithelium. Our long-term goal is to identify key missing components in this complex signaling puzzle to advance our understanding of the molecular mechanism underlying colon cancer. The objective of this proposal is to explore the role of a novel signaling pathway ICK-GSK3? in the development of colon cancer and tumor resistance to rapalogs. Our central hypothesis is that deregulated ICK-GSK3? signaling axis plays a pivotal role in intestinal neoplasia by transducing aberrant Wnt signals to mTOR hyper-activation through inhibitory phosphorylation of GSK3?-T7 and by mediating a novel feedback mechanism underlying rapamycin resistance in colon cancer therapy. This hypothesis was formulated on the basis of our recent published and preliminary data: 1) ICK, a Wnt transcriptional target, is highly over-expressed in human colon cancer specimens and mouse intestinal adenomas; 2) Knockdown of ICK expression in human colon cancer cells effectively attenuated malignant proliferation in vitro and subcutaneous tumor growth in vivo; 3) Disrupting ICK signaling in colon cancer cells impaired mTOR and Wnt activation; 4) GSK3?, a key component of both Wnt and mTOR pathways, is a novel substrate for ICK; 5) Elevated phosphorylation of GSK3?-T7 by ICK was observed in human CRC specimens as compared with adjacent normal mucosa and in human colon cancer cells after rapamycin treatment. To test this hypothesis, we propose the following two specific aims: Aim-1 will determine whether ICK is able to activate mTOR signaling in colon cancer cells through targeting a novel inhibitory phosphorylation site on GSK3?; Aim-2 will determine whether the ICK-GSK3? signaling axis is important for aberrant Wnt signal-induced intestinal malignancy and rapamycin resistance. Our proposed work is significant because our aims will address major knowledge gaps in our understanding of the mechanisms underlying Wnt activation of mTOR, inhibitory phosphorylation and regulation of GSK3?, and rapamycin resistance. Our proposed work is innovative because our aims may identify inhibitory phosphorylation of Thr-7 as a novel regulatory mechanism for GSK3?, and rapamycin-induced feedback up-regulation of GSK3?-T7 phosphorylation as an innovative mechanism underlying rapamycin resistance. Anticipated outcomes may exert significant impacts on the understanding of the signaling mechanisms underlying the onset and development of colon cancer as well as the design for more effective combination molecular therapy to overcome drug resistance and prevent tumor relapse.